DESCRIPTION: This proposal, which focuses on the IRS-signaling proteins discovered in the applicant's laboratory. IRS-signaling proteins are engaged and phosphorylated on tyrosine residues by the receptors for insulin and IGF-1, and various cytokines including IL-4, IL-9, IL-13, IFN-alpha/beta and growth hormone. IRS- signaling proteins regulate cellular growth and metabolism association with cellular signaling proteins which contain Src homology-2 domains (SH2-proteins). A full understanding of the IRS-signaling system and the elements it interacts with is scientifically and clinically important because diabetes and cancer are a contemporary health problem that affect million of Americans. Both diseases occur when normal signaling systems are disrupted: non-insulin dependent diabetes results when the signaling pathways become insensitive, whereas cancer results when pathways are unregulated. Insulin and IGF-1 also play an important role in inhibition of apoptosis, and IRS-signaling proteins appears to play a central role in this effect. Thus the study of novel downstream elements in the IRS-signaling system is relevant to both cancer and diabetes. The recent identification of IRS-2 provides new insight into the modular structure and function of the IRS-signaling system. Presumably, the IRS- proteins provide a means for signal amplification by eliminating the stoichiometric constraints encountered by most receptors which directly recruit SH2-proteins to their autophosphorylation sites. Moreover, IRS- proteins dissociate the intracellular signaling complex from the endocytic pathways of the activated receptor. The shared use of IRS- proteins by multiple receptors is likely to reveal important connections between various hormones and cytokines that were previously unrecognized, or observed but unexplained. The existence of additional signaling molecules based on the IRS-paradigm is likely. To continue this work during the next five years they propose the following specific aims: (1) Investigate the mechanism of receptor/IRS-proteins interaction by studying the function of the conserved NH2-terminus in IRS-1 and IRS-2; (2) Investigate the signaling specificity in IRS-proteins through multi-site phosphorylation of the COOH-terminal region; (3) Identify phosphotyrosine-independent signals in IRS-proteins that mediate the inhibition of apoptosis during insulin-stimulation; (4) Examine the role of IRS-signaling proteins in the regulation of glucose homeostasis in IRS-2(- /-) mice.